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PDBsum entry 1zjd

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protein Protein-protein interface(s) links
Hydrolase, blood clotting PDB id
1zjd
Jmol
Contents
Protein chains
237 a.a. *
57 a.a. *
Waters ×62
* Residue conservation analysis
PDB id:
1zjd
Name: Hydrolase, blood clotting
Title: Crystal structure of the catalytic domain of coagulation factor xi in complex with kunitz protease inhibitor domain of protease nexin ii
Structure: Catalytic domain of coagulation factor xi. Chain: a. Fragment: catalytic domain. Synonym: plasma thromboplastin antecedent. Pta. Fxi. Engineered: yes. Mutation: yes. Kunitz protease inhibitory domain of protease nexin ii. Chain: b.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: f11. Expressed in: pichia pastoris. Expression_system_taxid: 4922. Expression_system_cell_line: x-33. Gene: app, a4, ad1f11. Expression_system_cell_line: x-33
Biol. unit: Dimer (from PQS)
Resolution:
2.60Å     R-factor:   0.216     R-free:   0.255
Authors: L.Jin,D.Navaneetham,P.Pandey,J.E.Strickler,R.E.Babine, P.N.Walsh,S.S.Abdel-Meguid
Key ref:
D.Navaneetham et al. (2005). Structural and mutational analyses of the molecular interactions between the catalytic domain of factor XIa and the Kunitz protease inhibitor domain of protease nexin 2. J Biol Chem, 280, 36165-36175. PubMed id: 16085935 DOI: 10.1074/jbc.M504990200
Date:
28-Apr-05     Release date:   09-Aug-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P03951  (FA11_HUMAN) -  Coagulation factor XI
Seq:
Struc:
 
Seq:
Struc:
625 a.a.
237 a.a.*
Protein chain
Pfam   ArchSchema ?
P05067  (A4_HUMAN) -  Amyloid beta A4 protein
Seq:
Struc:
 
Seq:
Struc:
770 a.a.
57 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chain A: E.C.3.4.21.27  - Coagulation factor XIa.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Selective cleavage of Arg-|-Ala and Arg-|-Val bonds in factor IX to form factor IXa.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     nervous system development   2 terms 
  Biochemical function     catalytic activity     3 terms  

 

 
DOI no: 10.1074/jbc.M504990200 J Biol Chem 280:36165-36175 (2005)
PubMed id: 16085935  
 
 
Structural and mutational analyses of the molecular interactions between the catalytic domain of factor XIa and the Kunitz protease inhibitor domain of protease nexin 2.
D.Navaneetham, L.Jin, P.Pandey, J.E.Strickler, R.E.Babine, S.S.Abdel-Meguid, P.N.Walsh.
 
  ABSTRACT  
 
Factor XIa (FXIa) is a serine protease important for initiating the intrinsic pathway of blood coagulation. Protease nexin 2 (PN2) is a Kunitz-type protease inhibitor secreted by activated platelets and a physiologically important inhibitor of FXIa. Inhibition of FXIa by PN2 requires interactions between the two proteins that are confined to the catalytic domain of the enzyme and the Kunitz protease inhibitor (KPI) domain of PN2. Recombinant PN2KPI and a mutant form of the FXI catalytic domain (FXIac) were expressed in yeast, purified to homogeneity, co-crystallized, and the structure of the complex was solved at 2.6 angstroms (Protein Data Bank code 1ZJD). In this complex, PN2KPI has a characteristic, disulfide-stabilized double loop structure that fits into the FXIac active site. To determine the contributions of residues within PN2KPI to its inhibitory activity, selected point mutations in PN2KPI loop 1 11TGPCRAMISR20 and loop 2 34FYGGC38 were tested for their ability to inhibit FXIa. The P1 site mutation R15A completely abolished its ability to inhibit FXIa. IC50 values for the wild type protein and the remaining mutants were as follows: PN2KPI WT, 1.28 nM; P13A, 5.92 nM; M17A, 1.62 nM; S19A, 1.86 nM; R20A, 5.67 nM; F34A, 9.85 nM. The IC50 values for the M17A and S19A mutants were not significantly different from those obtained with wild type PN2KPI. These functional studies and activated partial thromboplastin time analysis validate predictions made from the PN2KPI-FXIac co-crystal structure and implicate PN2KPI residues, in descending order of importance, Arg15, Phe34, Pro13, and Arg20 in FXIa inhibition by PN2KPI.
 
  Selected figure(s)  
 
Figure 1.
FIGURE 1. The superimposition of the catalytic domain of FXIa in FXIac-PN2KPI and FXIa-benzamidine structures. A, a ribbon representation of the superimposition of the catalytic domain of FXIa in FXIac-PN2KPI (green) and FXIa-benzamidine (blue) structures. PN2KPI is colored in pink. The arrows indicate the loop containing residues 125-133 that adopt different conformations in each structure. B, a close-up view of only the superimposed catalytic domains of FXIa with several key residues that are discussed is shown in a ball-and-stick representation. The atoms of the FXIac-PN2KPI structure are colored as carbon atoms in green, nitrogen atoms in blue, oxygen atoms in red, and sulfur atoms in yellow. The FXI-benzamidine structure is colored in blue.
Figure 4.
FIGURE 4. Stereo view of the interface between FXI and PN2KPI. A, ribbon representation of FXIac-PN2KPI structure. The catalytic domain of FXI is in green with Arg37D and Tyr59A presented in ball-and-stick representation to indicate the two unique loops (residues 59-64 and residues 36-37D) of FXIa that interact with PN2KPI. B, close-up view of the interface between rhFXI-(370-607) and PN2KPI. All of the residues are in stick representations with oxygen atoms in red, nitrogen atoms in blue, sulfur atoms in yellow, and carbon atoms in green (FXIac) or pink (PN2KPI). There are two loops from PN2KPI interacting with FXI, residues 11TGPCRAMISR20 (P5-P5') in thick sticks and residues 34FYGGC^38 in thin sticks. Hydrogen bonds are presented in gray lines between the bonding atoms.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 36165-36175) copyright 2005.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20110423 J.Emsley, P.A.McEwan, and D.Gailani (2010).
Structure and function of factor XI.
  Blood, 115, 2569-2577.  
19920152 M.A.Salameh, J.L.Robinson, D.Navaneetham, D.Sinha, B.J.Madden, P.N.Walsh, and E.S.Radisky (2010).
The amyloid precursor protein/protease nexin 2 Kunitz inhibitor domain is a highly specific substrate of mesotrypsin.
  J Biol Chem, 285, 1939-1949.  
18186617 A.E.Schmidt, M.F.Sun, T.Ogawa, S.P.Bajaj, and D.Gailani (2008).
Functional role of residue 193 (chymotrypsin numbering) in serine proteases: influence of side chain length and beta-branching on the catalytic activity of blood coagulation factor XIa.
  Biochemistry, 47, 1326-1335.  
17884987 D.Samuel, H.Cheng, P.W.Riley, A.A.Canutescu, C.Nagaswami, J.W.Weisel, Z.Bu, P.N.Walsh, and H.Roder (2007).
Solution structure of the A4 domain of factor XI sheds light on the mechanism of zymogen activation.
  Proc Natl Acad Sci U S A, 104, 15693-15698.
PDB codes: 2j8j 2j8l
18020374 T.N.Miller, D.Sinha, T.R.Baird, and P.N.Walsh (2007).
A catalytic domain exosite (Cys527-Cys542) in factor XIa mediates binding to a site on activated platelets.
  Biochemistry, 46, 14450-14460.  
16699514 E.Papagrigoriou, P.A.McEwan, P.N.Walsh, and J.Emsley (2006).
Crystal structure of the factor XI zymogen reveals a pathway for transactivation.
  Nat Struct Mol Biol, 13, 557-558.
PDB code: 2f83
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